Patent GB-1298213-A (GB)
Title: A processs for the manufacture of tricyclic steroid precursors and novel tricyclic steroid intermediates useful therein
Inventor: SAUCY G
IPC: C07F9/54
Filed: 1969-11-20
Abstract: 1298213 Tricyclic steroid intermediates F HOFFMANN-LA ROCHE & CO AG 20 Nov 1969 [22 Nov 1968] 56792/69 Headings C2C C2P and C2U Compounds I where R 1  is 1-5 C alkyl; R 2  is 1-8 C alkyl; Z is a carbonyl group or a =C(OR 4 )R 5  group; R 4  is H, 1-8 C alkyl, 1-8 C alkoxy-1-8 C alkyl, phenyl-1-8 C alkyl, or tetrahydropyranyl; R 5  is H or 1-8 C aliphatic hydrocarbyl; and m is 1 or 2 are prepared by (a) protecting the free carbonyl group(s) of compounds II where R 3  is H or 1-8 C alkyl, alkaryl or aralkyl; Z 1  is a carbonyl group, (1-8 C alkylene)dioxymethylene, di - (1-8 C alkoxy) - methylene, phendioxymethylene or a =C(OR 6 )R 5  group; and R 5  is H, 1-8 C alkyl, 1-8 C alkoxy-1-8 C alkyl, phenyl. 1-8 C alkyl, 1-8 C acyl or tetrahydropyranyl; (b) selectively hydrogenating the isoxazolyl group to the corresponding vinylogous amide group; (c) hydrolysing the said amides and cleaving the thus obtained acyl derivatives with aqueous base to give, e.g. compounds VI where V is 1-8 C alkylenedioxymethylene, di- (1-8 C alkoxy)-methylene or phendioxymethylene, a corresponding mono or dithio group or a corresponding group wherein one O atom is replaced by =NH and Z 3  is as V with the addition that an O atom may be replaced by =C(OR 4 )R 5 ; and removing the protecting groups. Compounds VI are novel. Intermediates isolated are (A) ethyl #-pyrrolidino-crotonate prepared from ethyl acetoacetate and pyrrolidine; (B) 4 - carbo - ethoxy - 3,5 - dimethyl-isoxazole., prepared from (A) by reaction with nitroethane; (C) 3,5-dimethyl-4-hydroxymethyl-isoxazole, prepared by LiAlH 4  reduction of (B); (D) 4 - chloromethyl - 3,5 - dimethylisoxazole, prepared by reaction of (C) with thionyl chloride; (E) (3,5 - dimethyl - isoxazol - 4- ylmethyl)-triphenyl phosphonium chloride, prepared from (D) by reaction with triphenyl phosphine; (F) 3,5-dimethyl-4- [2-(3,4-dihydro- 2H - pyran - 2 - yl) - vinyl] - isoxazole, prepared from (E) by reaction first with sodium hydride, then with acrolein dimer; (G) 7- (3,5-dimethyl. isoxazol - 4 - yl) - 5 - hydroxy - #<SP>6</SP> - heptenoic acid lactone, prepared from (F) by reaction with sulphuric acid; (H) 7 - (3,5 - dimethyl - isoxazol-4-yl)-5-hydroxy-heptanoic acid lactone, prepared by reduction of (G); (J) 2-(2-diethylaminoethyl) - 6 - [2 - (3,5 - dimethyl - isoxazol - 4 - yl)- ethyl]-tetrahydropyran-2-ol, prepared by reaction of (H) with vinyl magnesium chloride; (K) 3-[2- (3,5 - dimethyl) - isoxazol - 4 - yl) - ethyl] - 6a#- methyl - 1 ,2,3,5,6,6a - hexahydrocyclopenta[f][1]- ] - benzopyran-7(8H)-one prepared by reaction of (J) with 2-methyl-cyclopentane-1,3-dione; (L) 3 - [2 - (3,5 - dimethyl - isoxazol - 4 - yl) - ethyl]- 7# - hydroxy - 6a# - methyl - 1,2,3,5,6,6a,7,8- octahydrocyclopenta[f][1]benzopyran, prepared by reduction of (K) with LiAlH 4 ; (M) trans-3-[2- (3,5 - dimethyl - isoxazol - 4 - yl) - ethyl] - 7#- hydroxy - 6a - methyl - 1,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta[f][1]benzopyran prepared by hydrogenation of (L); (N) trans - 3 - [2 - (3,5- dimethylisoxazol - 4 - yl) - ethyl] - 4α,7# - dihydroxy - 6a - methyl - perhydro - cyclopenta[f][1]- benzopyran, prepared by hydration of (M); (O trans - 4 - [3 - oxo - 5 - (3,5 - dimethyl - isoxazol - 4 - yl) - pentyl] - 1a - methyl - perhydroindan-1,5-diane prepared from (N) by reaction with CrO 3 ; and trans.- anti - 6 - [(3,5 - dimethyl - isoxazolyl - 4 - yl) - methyl] - 3a - methyl- 3,7 - dioxo - 1,2,3a,4,5,7,8,9,9a,9b - decahydro- 3H-benz[e]indene, prepared by cyclization af(O). The compounds I are intermediates for the production of steroids VII